Microbiology
Abstract
Acute-on-chronic liver failure (ACLF) is a leading cause of global liver-related mortality. Bacterial infection, especially in patients with decompensated cirrhosis (DC), commonly triggers ACLF and is difficult to treat with antibiotics. Therefore, finding alternative strategies for preventing and managing bacterial infection is an urgent priority. Here, we observed that infected DC patients and ACLF mice exhibited lower fecal panose levels than uninfected controls. Megamonas funiformis (M. funiformis), with 4α-glucanosyltransferase (4αGT) as a key enzyme for panose production, was identified as a potential panose producer. Animal experiments demonstrated that panose efficiently reduced liver injury and extended survival in ACLF mice by mitigating bacterial infection. Further results revealed that panose enhanced resistance to bacterial infection by inhibiting oxidative stress-induced gut barrier disruption, thereby limiting bacterial dissemination. Mechanistically, panose interacted with the solute carrier family 7 member 11 (SLC7A11, also known as xCT) protein to boost antioxidant glutathione (GSH) levels in intestinal epithelial cells. These findings highlight panose's potential in preventing bacterial infection, offering a valuable insight into mitigating ACLF progression.
Authors
Jiaxin Li, Shihao Xie, Meiling Chen, Changze Hong, Yuqi Chen, Fengyuan Lyu, Niexin Tang, Tianqi Chen, Lingyan Zhao, Weihao Zou, Hongjuan Peng, Jingna Bao, Peng Gu, Bernd Schnabl, Jinjun Chen, Peng Chen
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI180826.
Abstract
Accumulating evidence implicates the gut microbiome (GMB) in the pathogenesis and progression of Alzheimer’s disease (AD). We recently showed that the GMB regulates reactive astrocytosis and Aβ plaque accumulation in male APPPS1-21 AD model mice. Yet, the mechanism(s) by which GMB perturbation alters reactive astrocytosis in a manner that reduces Aβ deposition remain unknown. Here, we performed metabolomics on plasma from mice treated with antibiotics (abx) and identified a significant increase in plasma propionate, a gut-derived short chain fatty acid, only in male mice. Administration of sodium propionate reduced reactive astrocytosis and Aβ plaques in APPPS1-21 mice, phenocopying the abx-induced phenotype. Astrocyte-specific RNA sequencing on abx and propionate treated mice showed reduced expression of pro-inflammatory and increased expression of neurotrophic genes. Next, we performed flow cytometry experiments where we found abx and propionate decreased peripheral RAR-related orphan receptor-γ (Rorγt)+ CD4+ (Th17) cells and IL-17 secretion, which positively correlated with reactive astrocytosis. Lastly, using an IL-17 monoclonal antibody to deplete IL-17, we found that propionate reduces reactive astrocytosis and Aβ plaques in an IL-17-dependent manner. Together, these results suggest that gut-derived propionate regulates reactive astrocytosis and Aβ amyloidosis by decreasing peripheral Th17 cells and IL-17 release. Thus, propionate treatment or strategies boosting propionate production may represent novel therapeutic strategies for AD.
Authors
Sidhanth Chandra, Jelena Popovic, Naveen K. Singhal, Elyse A. Watkins, Hemraj B. Dodiya, Ian Q. Weigle, Miranda A. Salvo, Abhirami Ramakrishnan, Zhangying Chen, James T. Watson, Aashutosh Shetti, Natalie Piehl, Xiaoqiong Zhang, Leah K. Cuddy, Katherine R. Sadleir, Steven J. Schwulst, Murali Prakriya, David Gate, Sangram S. Sisodia, Robert Vassar
Abstract
Authors
Tran Xuan Ngoc Huy, Huynh Tan Hop
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI185430.
Abstract
As antimicrobial resistance rises, new antibacterial candidates are urgently needed. Using sequence space information from over 14,743 functional antimicrobial peptides (AMPs), we improved the antimicrobial properties of citropin 1.1, an AMP with weak anti-methicillin resistant Staphylococcus aureus (MRSA) activity, producing a short and potent anti-staphylococcal peptide, CIT-8 (13 residues). At 40 μg/ml, CIT-8 eradicated 1 × 108 drug-resistant MRSA and VRSA (vancomycin resistant S. aureus) persister cells within 30 mins of exposure and reduced the number of viable biofilm cells of MRSA and VRSA by 3 log10 and 4 log10 in established biofilms, respectively. CIT-8 (at 32 μg/ml) depolarized and permeated the S. aureus MW2 membrane. In a mouse model of MRSA skin infection, CIT-8 (2% w/w in petroleum jelly) significantly reduced the bacterial burden by 2.3 log10 (p < 0.0001). Our methodology accelerates AMP design by combining traditional peptide design strategies, such as truncation, substitution, and structure-guided alteration, with machine learning (ML)-backed sequence optimization.
Authors
Biswajit Mishra, Anindya Basu, Fadi Shehadeh, LewisOscar Felix, Sai Sundeep Kollala, Yashpal Singh Chhonker, Mandar T. Naik, Charilaos Dellis, Liyang Zhang, Narchonai Ganesan, Daryl J. Murry, Jianhua Gu, Michael B. Sherman, Frederick M. Ausubel, Paul P. Sotiriadis, Eleftherios Mylonakis
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI170690.
Abstract
Colistin (COL) is a cationic cyclic peptide that disrupts negatively-charged Gram-negative bacterial cell membranes and frequently serves as an antibiotic of last resort to combat multidrug-resistant Gram-negative bacterial infections. Emergence of the horizontally transferable plasmid-borne mobilized colistin resistance (mcr) determinant and its spread to Gram-negative strains harboring extended-spectrum β-lactamase and carbapenemase resistance genes threatens futility of our chemotherapeutic arsenal. COL is widely regarded to have zero activity against mcr+ strains based on standard antimicrobial susceptibility testing (AST) performed in enriched bacteriological growth media; consequently, the drug is withheld from patients with mcr+ infections. However, these standard testing media poorly mimic in vivo physiology and omit host immune factors. Here we observed that COL exhibits bactericidal activities against mcr+ isolates of Escherichia coli, Klebsiella pneumoniae, and Salmonella enterica in tissue culture media containing the physiological buffer bicarbonate. Moreover, COL promoted serum complement deposition on the mcr-1+ Gram-negative bacterial surface and synergized potently with active human serum in pathogen killing. At COL concentrations readily achievable with standard dosing, the peptide antibiotic killed mcr-1+ E. coli, K. pneumoniae, and S. enterica in freshly isolated human blood and proved effective as monotherapy in a murine model of E. coli bacteremia. Our results suggest that COL, currently ignored as a treatment option based on traditional AST, may in fact benefit patients with mcr-1+ Gram negative infections based on evaluations performed in a more physiologic context. These concepts warrant careful consideration in the clinical microbiology laboratory and for future clinical investigation of their merits in high-risk patients with limited therapeutic options.
Authors
Monika Kumaraswamy, Angelica Riestra, Anabel Flores, Samira Dahesh, Fatemeh Askarian, Satoshi Uchiyama, Jonathan Monk, Sean Jung, Gunnar Bondsäter, Victoria Nilsson, Melanie Chang, Jürgen B Bulitta, Yinzhi Lang, Armin Kousha, Elisabet Bjånes, Natalie Chavarria, Ty'Tianna Clark, Hideya Seo, George Sakoulas, Victor Nizet
Citation Information: J Clin Invest. 2025;135(8):e182467. https://doi.org/10.1172/JCI182467.
Abstract
Plasmacytoid dendritic cells (pDCs), professional type I IFN–producing cells, have been implicated in host responses against bacterial infections. However, their role in host defense is debated, and the operating molecular mechanisms are unknown. Certain signaling lymphocyte activation molecule family (SLAMF) members act as microbial sensors and modulate immune functions in response to infection. Here, human blood transcriptomic analyses reveal the involvement of SLAMF7 and SLAMF8 in many infectious diseases, with elevated levels associated with type I IFN responses in salmonellosis and brucellosis patients. We further identify SLAMF7 and SLAMF8 as key regulators of human pDC function. They activate pDC maturation and cytokine production during infection with bacteria that induce acute (Salmonella) or chronic (Brucella) inflammation. SLAMF7 and SLAMF8 signal through NF-κB, IRF7, and STAT-1, and limit mitochondrial ROS accumulation upon Salmonella infection. Remarkably, this SLAMF7/8-dependent control of mitochondrial ROS levels favors bacterial persistence and NF-κB activation. Overall, our results unravel essential shared multifaceted roles of SLAMF7 and SLAMF8 in finely tuning human pDC responses to intracellular bacterial infections with potential for future diagnostic and therapeutic applications.
Authors
Joaquín Miguel Pellegrini, Anne Keriel, Laurent Gorvel, Sean Hanniffy, Vilma Arce-Gorvel, Mile Bosilkovski, Javier Solera, Stéphane Méresse, Sylvie Mémet, Jean-Pierre Gorvel
Abstract
Authors
Sarah J. Morgan, Ellis Coulter, Hannah L. Betts, George M. Solomon, John P. Clancy, Steven M. Rowe, David P. Nichols, Pradeep K. Singh
Citation Information: J Clin Invest. 2024. https://doi.org/10.1172/JCI182769.
Abstract
Authors
Jade Bath, Elisabet Bjånes, Cengiz Goekeri, Jeff Hsiao, Deniz Uzun, Geraldine Nouailles, Victor Nizet, Katharina Ribbeck
Citation Information: J Clin Invest. 2024. https://doi.org/10.1172/JCI176466.
Abstract
BACKGROUND. Features of consumptive coagulopathy and thromboinflammation are prominent in cerebral malaria (CM). We hypothesized that thrombogenic autoantibodies contribute to a procoagulant state in CM. METHODS. Plasma from children with uncomplicated malaria (UM, n = 124) and CM (n = 136) was analyzed by ELISA for a panel of 8 autoantibodies including anti-Platelet Factor 4/polyanion (anti-PF4/P), anti-Phospholipid, anti-Phosphatidylserine, anti-Myeloperoxidase, anti-Proteinase 3, anti-dsDNA, anti-Beta-2-Glycoprotein I (β2GPI), and anti-Cardiolipin. Non-malaria coma (NMC, n = 49) and healthy controls (HC, n = 56) were assayed for comparison. Associations with clinical and immune biomarkers were determined using univariate and logistic regression analyses. RESULTS. Median anti-PF4/P and anti-PS IgG levels were elevated with malaria infection relative to HC (P < 0.001) and NMC (PF4/P: P < 0.001). Anti-PF4/P IgG levels were elevated in CM (median = 0.27, IQR: 0.19–0.41) compared to UM (median = 0.19, IQR: 0.14–0.22, P ≤ 0.0001). Anti-PS IgG levels did not differ between UM and CM (P = 0.39). When CM cases were stratified by malaria retinopathy (Ret) status, levels of anti-PF4/P IgG correlated negatively with peripheral platelet count in Ret+ CM cases (Rs = 0.201, P = 0.04) and associated positively with mortality (OR = 15.2, 95% CI: 1.02–275, P = 0.048). Plasma from CM patients induced a greater platelet activation capacity in an ex-vivo assay relative to plasma from UM patients (P = 0.02). Platelet activation was associated with anti-PF4/P IgG levels (Rs = 0.293, P = 0.035). CONCLUSIONS. Thrombosis mediated by elevated anti-PF4/P autoantibodies may be one mechanism contributing to the clinical complications of CM.
Authors
Iset M. Vera, Anne Kessler, Visopo Harawa, Ajisa Ahmadu, Thomas E. Keller, Stephen T.J. Ray, Terrie E. Taylor, Stephen J. Rogerson, Wilson L. Mandala, Morayma Reyes Gil, Karl B. Seydel, Kami Kim
Citation Information: J Clin Invest. 2023. https://doi.org/10.1172/JCI167957.
Abstract
BACKGROUND. Lung infections are among the most consequential manifestations of cystic fibrosis (CF) and are associated with reduced lung function and shortened survival. Drugs called CFTR modulators improve activity of dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) channels, which is the physiological defect causing CF. However, it is unclear how improved CFTR activity affects CF lung infections. METHODS. We performed a prospective, multicenter, observational study to measure the effect of the newest and most effective CFTR modulator, elexacaftor/tezacaftor/ivacaftor (ETI) on CF lung infections. We studied sputum from 236 people with CF during their first 6 months of ETI using bacterial cultures, PCR and sequencing. RESULTS. Mean sputum densities of Staphylococcus aureus, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Achromobacter and Burkholderia spp. decreased by 2-3 log10 CFU/ml after 1 month of ETI. However, most participants remained culture-positive for the pathogens cultured from their sputum before starting ETI. In those becoming culture-negative after ETI, the pathogens present before treatment were often still detectable by PCR months after sputum converted to culture-negative. Sequence-based analyses confirmed large reductions in CF pathogen genera, but other bacteria detected in sputum were largely unchanged. ETI treatment increased average sputum bacterial diversity and produced consistent shifts in sputum bacterial composition. However, these changes were caused by ETI-mediated decreases in CF pathogen abundance rather than changes in other bacteria. CONCLUSIONS. Treatment with the most effective CFTR modulator currently available produced large and rapid reductions in traditional CF pathogens in sputum, but most participants remain infected with the pathogens present before modulator treatment. TRIAL REGISTRATION. The trial registered at www.ClinicalTrials.gov as NCT04038047. FUNDING. This study was funded by the Cystic Fibtosis Foundation (PROMISE-MICRO18K1 and SINGH19R0) and NIH (R01HL148274).
Authors
David P. Nichols, Sarah J. Morgan, Michelle Skalland, Anh T. Vo, Jill M. Van Dalfsen, Sachinkumar B.P. Singh, Wendy Ni, Lucas R. Hoffman, Kailee McGeer, Sonya L. Heltshe, John P. Clancy, Steven M. Rowe, Peter K. Jorth, Pradeep K. Singh
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